The association between cost sharing, prior authorization, and specialty drug utilization: A systematic review

BACKGROUND: Specialty drugs are identified by high monthly costs and complexity of administration. Payers use utilization management strategies, including prior authorization and separate tiers with higher cost sharing, to control spending. These strategies can negatively impact patients’ health outcomes through treatment initiation delays, medication abandonment, and nonadherence. OBJECTIVE: To examine the effect of patient cost sharing on specialty drug utilization and the effect of prior authorization on treatment delay and specialty drug utilization. METHODS: We conducted a literature search in the period between February 2021 and April 2022 using PubMed for articles published in English without restriction on date of publication. We included research papers with prior authorization and cost sharing for specialty drugs as exposure variables and specialty drug utilization as the outcome variable. Studies were reviewed by 2 independent reviewers and relevant information from eligible studies was extracted using a standardized form and approved by 2 reviewers. Review papers, opinion pieces, and projects without data were excluded. RESULTS: Forty-four studies were included in this review after screening and exclusions, 9 on prior authorization and 35 on cost sharing. Patients with lower cost sharing via patient support programs experienced higher adherence, fewer days to fill prescriptions, and lower discontinuation rates. Similar outcomes were noted for patients on low-income subsidy programs. Increasing cost sharing above $100 was associated with up to 75% abandonment rate for certain specialty drugs. This increased level of cost sharing was also associated with higher discontinuation rates and odds. At the same time, decreasing out-of-pocket costs increased initiation of specialty drugs. However, inconsistent results on impact of cost sharing on medication possession ratio (MPR) and proportion of days covered (PDC) were reported. Some studies reported a negative association between higher costs and MPR and PDC; however, MPR and PDC of cancer specialty drugs did not decrease with higher costs. Significant delays in prescription initiation were reported when prior authorization was needed. CONCLUSIONS: Higher levels of patient cost sharing reduce specialty drug use by increasing medication abandonment while generally decreasing initiation and persistence. Similarly, programs that reduce patient cost sharing increase initiation and persistence. In contrast, cost sharing had an inconsistent and bidirectional effect on MPR and PDC. Prior authorization caused treatment delays, but its effects on specialty drug use varied. More research is needed to examine the effect of cost sharing and prior authorization on long-term health outcomes.


OBJECTIVE:
To examine the effect of patient cost sharing on specialty drug utilization and the effect of prior authorization on treatment delay and specialty drug utilization.

METHODS:
We conducted a literature search in the period between February 2021 and April 2022 using PubMed for articles published in English without restriction on date of publication. We included research papers with prior authorization and cost sharing for specialty drugs as exposure variables and specialty drug utilization as the outcome variable. Studies were reviewed by 2 independent reviewers and relevant information from eligible studies was extracted using a standardized form and approved by 2 reviewers. Review papers, opinion pieces, and projects without data were excluded.

RESULTS:
Forty-four studies were included in this review after screening and exclusions, 9 on prior authorization and 35 on cost sharing. Patients with lower cost sharing via patient support programs experienced higher adherence, fewer days to fill prescriptions, and lower discontinuation rates. Similar outcomes were noted for patients on low-income subsidy programs. Increasing cost sharing above $100 was associated with up to 75% abandonment rate for certain specialty drugs. This increased level of cost sharing was also associated with higher discontinuation rates and odds. At the same time, decreasing out-of-pocket costs increased initiation of specialty drugs. However, inconsistent results on impact of cost sharing on medication possession ratio (MPR) and proportion of days covered (PDC) were reported. Some studies reported a negative association between higher costs and MPR and PDC; however, MPR and PDC of cancer specialty drugs did not decrease with higher costs. Significant delays in prescription initiation were reported when prior authorization was needed.

CONCLUSIONS:
Higher levels of patient cost sharing reduce specialty drug use by increasing medication abandonment while generally decreasing initiation and persistence. Similarly, programs that reduce patient cost sharing increase initiation and persistence. In contrast, cost sharing had an inconsistent and bidirectional effect on MPR and PDC. Prior authorization caused treatment delays, but its effects on

Plain language summary
The cost of some specialty drugs is very high. Insurance companies try to control these costs by having patients pay more for the drugs and making it so that the patient needs approval before using the medicine. In this review, we looked at how much higher patient costs and requiring approval kept patients from using these specialty drugs that the physician ordered.

Implications for managed care pharmacy
Payers can manage and reduce the cost of highly expensive specialty drugs in the short term through strategies such as increasing cost sharing and requiring prior authorization. However, these strategies have some negative impacts on patients' utilization of specialty drugs, which may, in the long term, increase payer spending to manage complications that result from delayed initiation or increased abandonment of these drugs.
Specialty drugs are medications distinguished by their high production costs, their requirements for special manufacturing, distribution, or handling, and their ability to treat and/or manage rare conditions such as cancer, multiple sclerosis (MS), or rheumatoid arthritis (RA). 1 Historically, most specialty drugs were derived from biologic sources and injected or infused in clinical settings, but oral dosage forms and self-injectables are becoming increasingly available in the market. The Centers for Medicare and Medicaid Services uses a cost threshold to define specialty drugs; for 2023, the threshold is $830 per month based on 30-day equivalent ingredient cost. 2 Payers often target specialty drugs for additional management because of their high cost compared with traditional medications. The percentage of patients who use specialty drugs is small, ranging from 1% to 5%, 3,4 but the cost is high. It is estimated that $301 billion was spent on specialty drugs in 2021 in the United States, an increase of 43% since 2016. 5 By 2021, spending for specialty drugs represented approximately 40% of retail drug spending and nearly 70% of nonretail drug spending. 5 To manage prescription drug spending, payers use many tactics that can be combined under the term "utilization management (UM)." One UM strategy is categorizing specialty drugs in a separate tier that requires patients to pay higher copayment or coinsurance, resulting in higher patient out-of-pocket (cost sharing) costs compared with nonspecialty drugs. 6,7 It is estimated that 49% of covered workers are in a plan with a separate tier for specialty drugs. 8 Plans without a separate tier for specialty drugs typically place them in the highest cost-sharing tier. Coinsurance can be particularly problematic because patients pay a percentage of the high specialty drug prices. Of the covered workers facing a separate specialty drug tier, 42% had coinsurance with an average coinsurance rate of 27%. 8 For plans without a separate tier for specialty drugs, 43% of covered workers had coinsurance for fourth-tier drugs and the average coinsurance percentage was 32%. 8 It is estimated that patients spend approximately $35.8 billion annually in drug cost sharing. 9 Another UM technique is prior authorization (PA), in which insurers require patients to obtain approval before using a drug or medical service. The PA process requires providers to complete a form and wait for a response of approval (or denial) from the insurer. The PA request must be approved for the drug or service to be a covered benefit. According to 2020 Medication Access Report, 37% of prescriptions denied because of PA requirements were abandoned. 10 Although these UM tactics can help payers to control expenditures, they potentially affect specialty drug use, particularly medication nonadherence. Measures of nonadherence include initiation, abandonment, persistence, continuity gaps, proportion of days covered (PDC), and medication possession ratio (MPR). Medication initiation is defined as the first fill or any fill of any drug prescription within a predefined period of time (ie, 90 days, 180 days, or 2 years as defined by Doshi et al and Romley et al). [11][12][13] Abandonment is failure to fill a prescription (ie, prescription is left at the pharmacy and never picked up), a reversed claim, or an unpaid claim within 90 days or 180 days of prescription date. 14,15 Persistence is defined as continuation of and time of medication use after the first refill. Continuity gaps measure whether patients are without their medication for a specified length of time. PDC and MPR are 2 quantitative methods that are used to measure nonadherence. MPR is the sum of days supply dispensed within a period of time divided by the number of days in the time period, which could exceed 100%. PDC is the proportion of time period in which medication supply was available. PDC is more conservative than MPR and never exceeds 100%. A cut point of 0.8 is commonly used to set the MPR or PDC threshold for an acceptable level of adherence. [16][17][18] An earlier systematic review published by Doshi et al. reviewed evidence regarding the association between cost sharing and specialty drugs utilization for RA, MS, and cancer. 19 This review updates the review by Doshi et al and expands the scope to include any specialty drug indication and the impact of PA.
The objectives for this systematic review of the literature were to examine (1) the effect of patient cost sharing on specialty drug utilization and (2) the effect of PA on treatment delay and specialty drug utilization.

Methods
We conducted a literature search using PubMed for all articles published in English without restriction on date of publication, in the period between February 2021 and April 2022. The first primary search was based on combination of 2 key words; the first included "specialty drug," "specialty medication," "biologic," or "biopharmaceutical" and 1 of the following: PA, abandonment, patient cost, claims, outof-pocket, adherence, utilization, initiation, copayment, Effects on Initiation, Abandonment, and Time to Use. Cost sharing is associated with changes in specialty drugs initiation and prescription abandonment. With low cost sharing (between $0 and $50), the abandonment rate for specialty drugs was 1.3%-10%. [13][14][15]42,43 Increasing patient cost sharing above $100 was associated with a 32%-75% abandonment rate for specialty drugs. [13][14][15] Compared with patients who paid less than $100, patients who paid $100 or more were 2-26 times more likely to abandon their prescriptions. 42,44 A similar pattern was noticed between cost sharing and medication initiation. Increasing the cost sharing was associated with delayed initiation of medications. [11][12][13][45][46][47] Included studies used different cutoff points to define delayed initiation. These points ranged between 90 days and 2 years. The delayed initiation of oral anticancer specialty drugs was approximately 18% for patients who paid more than $2,000, 13 but it reached 35% for some medications such as imatinib (annual out-of-pocket cost of $8,400) and even up to 70% for thalidomide (annual out-of-pocket cost of $13,700). 45 Romely et al 11 found that the impact of an 18% cost sharing increase delayed the initiation of MS diseasemodifying agents by 13% within 2 years of initial diagnosis. Goldman 46 reported that decreasing cost sharing by 20% increased initiation by 5%. This effect was affirmed by the simulation by Ozmainkowski et al, 47 in which MS medication (namely, interferon and glatiramer) initiation increased by 55% when the copayment was reduced by 50%. However, initiation decreased by 33% when the copayment was increased by 50%. If the copayment was set at $0, the probability of initiation increased to 70%.

Effects on Persistence.
Cost sharing was also associated with medication persistence. As cost sharing increased, the discontinuation rate of imatinib, adalimumab, etanercept and infliximab increased by 4%-26% when compared with groups with lower copayments. 12,45,48,49,52 The hazard ratio of discontinuation with a $25-$250 increase in copayments for the MS disease-modifying agents, etanercept and adalimumab, ranged between 1.57 and 3.01. 50,51 In terms of discontinuation odds, Hopson et al 15 showed that patients with RA who paid more than $250 had 0.27 odds of specialty drugs refilling when compared with patients who paid less than $250. Bonafede et al 53 also found that higher etanercept and RA biologics copayments were associated with a higher rate of discontinuation, but the association was not statistically significant. Kaisang et al 45 compared the risk of discontinuation for several kinds of cancer specialty drugs. They found that with each $10 extra copayment, the risk of discontinuation increased by 13% and 14% for imatinib and erlotinib, respectively. However, the risk of discontinuation decreased (ie, increased persistence) by 26% for anastrozole and letrozole with the coinsurance, deductibles, drug spending, specialty tier, tiered benefit, or benefit design. The second search aimed to identify specific classes of medications that are classified as "specialty drug" and the diseases they are prescribed to manage. The search included a combination of the former words, in addition to autoimmune, rheumatoid, irritable bowel disease (IBD), Crohn's, ulcerative colitis, psoriasis, cancer, PCSK9i, or tumor necrosis factor. References of included papers were checked for eligible articles.
Studies from search results were reviewed independently by 2 members of the research team (Mr Ismail and Dr Urmie) to identify eligible studies through applying predefined inclusion criteria. Disagreements on inclusion were resolved through discussion and mutual agreement. An abstraction form was used to collect data from the studies. All abstracted information was reviewed and approved by 2 reviewers, independently (Mr Ismail and Dr Urmie).
We included research papers with PA and/or cost sharing (including out-of-pocket cost, copayment, and coinsurance) as the exposure variable of interest (independent variable) and specialty drug use as the outcome of interest. Specialty drug use encompassed multiple measures of medication nonadherence, including time to initiation, initiation, abandonment, persistence, discontinuation, PDC, and MPR. We excluded papers that were literature reviews, opinion pieces, analysis of trends, and projects without data. Studies were grouped by exposure variable (cost sharing and PA) for syntheses of evidence. The patient support program studies were only included if they had a reduced patient cost sharing component.
Institutional review board approval was not needed because this project is a systematic review of published literature.

PATIENT COST SHARING
Patient cost sharing includes copayments, coinsurance, and deductibles. Studies on cost sharing were mostly crosssectional studies comparing specialty drug use across different cost-sharing levels, but a few studies examined the effect of cost sharing changes.
The association between cost sharing, prior authorization, and specialty drug utilization: A systematic review were reported by Darkow, 56 Kim, 50 and Liu. 57 Darkow et al 56 reported a 5% increase in the MPR for imatinib with a $38 increase in cost sharing, but the increase was statistically insignificant. Kim et al 50 studied several specialty drugs with multiple indications. They found that PDC for anticancer, antiinflammatory, and MS drugs did not change following up to a $250 increase in cost sharing, but there was a very small decrease (approximately 0.04) in PDC for immunosuppressants with a similar cost change. Higher copayments weakly reduced adherence to adalimumab (approximately 0.01) as reported by Liu et al. 57

COST SHARING REDUCTION VIA A PSP
Some pharmaceutical manufacturers and specialty pharmacies offer PSPs to assist patients with specialty drug use. These broader programs may offer multiple forms of support; this literature review focused on PSPs that included financial assistance with specialty drug cost sharing.
The impact of adalimumab-treated PSPs is well examined in the literature. Following patients in these programs for 12 months, PDC rates of adalimumab significantly increased, with increases between 14% and 29%. 20,21,23,24 Approximately 44% of patients in adalimumab PSP were able to maintain PDC above 80% threshold, significantly higher than the 26% of adherent patients who were not in a patient support program. Moreover, they were able to continue using adalimumab for 134 extra days when compared with patients not participating in such programs as reported by Brixner et al. 21 Also, discontinuation rates were significantly reduced at 12 months. In general, the amount of reduction ranged between 12% and 30%, 21,24 with a reduction of 70% reported by Brixner et al. 20 This high rate differed across indications of adalimumab: 66% for RA, same extra $10 copayment. 45 It is worth mentioning that the anastrozole and letrozole sample, whose size was 10 times larger than the sample size of imatinib and erlotinib users, was restricted to female beneficiaries who used these medications to treat breast cancer. Additionally, there was a higher noncancer drug cost burden for imatinib and erlotinib users. 45 Effects on Adherence as Measured by MPR and PDC. The impact of cost sharing on specialty drug MPR and PDC was inconsistent. Higher cost sharing has often been associated with lower PDC and MPR for biologic disease-modifying antirheumatic drugs (including etanercept and adalimumab), imatinib, and MS drugs. 49,51,52,54,55 Dusetzina et al 52 found that higher copayments were associated with decreased PDC (ie, 82% vs 87% PDC for higher and lower copayments, respectively). Dor et al 58 examined the association between different types of cost sharing and adherence to MS drugs. They found that a 10% increase in coinsurance decreased the MPR by 8.6%, but copayment increases did not affect MPR. Sherman et al 48 reported that implementation of a program that reduced patient cost sharing significantly decreased PDC.
Interestingly, insignificant or very weak associations between costsharing changes and MPR or PDC

Adherence (PDC) and initiation
No significant difference in adherence or initiation adjusted RR between those who received and did not receive cost subsidy. 72% for IBD, and 76% for ankylosing spondylitis. 20 Hawkes et al 22 showed that patient support programs reduced abandonment rate by 43%. Patients in these programs took approximately 50% fewer days (ie, 7 days) to fill their first prescription compared with nonparticipants (ie, 14 days), 22 and the rate of refills for adalimumab was increased by 36%. 20

COST-SHARING REDUCTION VIA THE MEDICARE PART D LOW-INCOME SUBSIDY PROGRAM
One subcategory of cost-sharing studies was studies examining the effects of LIS in Medicare Part D. LIS programs are designed to help qualified patients with their out-of-pocket costs by lowering the medications coinsurance and copayments. Dusetzina et al 30 found that noninitiation of drugs among non-LIS patients was 21% for hepatitis C drugs, 28% for cancer drugs and 67% for hypercholesterolemia drugs. Non-LIS patients were 37% less likely to fill their prescriptions within 90 days. 30 Compared with LIS-eligible patients, it was found that non-LIS patients have lower odds of initiating their specialty drugs prescriptions. These odds were 0.49 for oral therapies, 0.52 for renal carcinoma targeted therapies, and 0.69 for RA biologics. 25,29 Lower fill rates for specialty drugs used to treat RA, renal cell carcinoma, and chronic myelogenous leukemia (such as tyrosine kinase inhibitors) were also noted for non-LIS groups with odds ratios of filling between 0.55 and0.59. 25,26,29 Doshi et al 26 found that non-LIS groups consistently took longer periods of times (almost twice the time of LIS patients) to initiate tyrosine kinase inhibitors for chronic myelogenous leukemia within 1, 3, and 6 months of prescribing. LISreceiving patients had higher tyrosine kinase inhibitor PDC (risk ratio [RR] = 1.12; P > 0.05), lower time to initiate (RR = 1.35; P < 0.05) and higher initiation within 180 days (RR = 1.08; P > 0.05) when compared with non-LIS patients, as reported by Winn et al. 31 In a separate study, Doshi et al 27 found that non-LIS patients had 33% lower odds of adherence (ie, PDC > 0.8) to psoriasis biologics when compared with LIS patients. They also experienced almost double the odds of discontinuation.
Non-LIS patients diagnosed with MS also experienced 1.61 times the odds of LIS patients of 30-day continuity gaps in Part D medications on transitioning from the low cost sharing period into the high cost sharing period. And even larger effect was found for patients with RA, where non-LIS patients experienced 2.75 times the odds of a 30-day continuity gap compared with LIS patients. 28 Continuity gaps in this study were measured by whether the claims data indicated the presence of at least 1 continuous gap of 30 days or more with no supply of Part D MS or RA medications. 28 designs face increasingly higher out-of-pocket costs. Rome et al 60 reported that the average launch price for a new drug increased from $2,155 per year in 2008 to $180,007 per year in 2021.
Although patient cost sharing generally had negative effects on specialty drugs initiation and abandonment, the effects of cost sharing on MPR and PDC were more mixed. There are different possible explanations for these mixed effects. Specialty drugs are often used for medical conditions that are either life-threatening or have significant negative effects on quality of life, so patients who start a specialty drug may be reluctant to take less than prescribed because they do not want to lose its beneficial effects. However, an alternative explanation is that the reported patient cost-sharing amount is not the true patient cost sharing amount because of manufacturer copay offset programs that reduce patient cost sharing for some brand-name medications. These programs typically are open to privately insured patients of all income levels. They substantially reduce patient out-of-pocket costs and are widely used for some specialty drugs. 44,61 Cost-sharing reductions from copayment offset programs may not have been fully captured in claims data. Another possible explanation is that some of the MPR and PDC studies were from patient support programs that included patient adherence support beyond cost sharing assistance, making it difficult to disentangle effects of the cost sharing from effects of the broader support program.

PRIOR AUTHORIZATION
This review examined the impact of PAs on medication use. The prevalence of PA has increased substantially over time. 62 A benefit of PA is that it can potentially reduce the use of inappropriate or expensive medications, but it is costly in terms of provider time and potential delays in treatment initiation. Our review of the literature found that PA was associated with treatment delay of up to 31 days. Although not an a priori outcome of interest in our study, it was interesting to note that prior authorization approval rates varied from 19% to 97.5%. [38][39][40] For medications for which the approval rate is very high, the small reduction in drug use may not justify the cost of the PA process and the delay in initiating therapy, although it is possible that it deters providers from seeking approval for patients who they know do not meet the PA criteria. In situations in which the PA approval rate is very low, the PA requirement would result in substantial prescription costsavings. It was beyond the scope of our review to determine the appropriateness of the medication denials, but inappropriately denying medications may have unintended long-term consequences for health and health care costs, which would be relevant to multiple stakeholders, including payers.

PRIOR AUTHORIZATION
PA requirements created delays in treatment but had somewhat mixed effects on specialty drug utilization.
Prior authorization was needed for 47%-71% of RA and asthma biologics. 34,37 It took between 6.7 days and 21 days for insurance companies and payers to process PA requests. 34,35,40 Several studies reported that prior authorization increased time to treatment initiation. This increase ranged between 3.6 days for cancer drugs 39 and up to 31 days for RA and inflammatory bowel disease biologics. 33,37 Ultimately, the delay caused by prior authorization lowered initiation of dermatologic treatment by 26%, 35 and patients filled only 14% of non-PA-approved prescriptions, compared with 78% of approved prescriptions. 35 In contrast, Boytsov 36 did not find any significant difference in adherence (defined as PDC > 0.8) to RA biologic disease-modifying antirheumatic drugs or treatment effectiveness because of PA. Fischer et al 41 also showed that PA in state Medicaid programs initially decreased the use of RA biologics (eg. adalimumab, etanercept), but biologic use subsequently returned to levels similar to state Medicaid programs that did not have PA requirements.

Discussion
Higher levels of patient cost sharing consistently resulted in lower levels of medication initiation and mostly reduced persistence, but the effect of cost sharing on MPR and PDC was inconsistent. PA led to some treatment delays, but its effects on specialty drug utilization varied.

COST SHARING AND ADHERENCE
Patient cost sharing seems to have a particularly strong association with rates of medication initiation and abandonment. In the studies included in our literature review, cost sharing of $100 or more was associated with abandonment rates between 32% and 75%. A broader study on the effect of cost sharing on abandonment of both specialty and nonspecialty drugs found that abandonment rates increased steadily as patient cost sharing increased and reached 69% when cost sharing was $250 or more. 59 As a result of the Affordable Care Act, all employer plans have out-of-pocket maximums for covered health care expenses and some employers have implemented separate prescription drug out-of-pocket maximums. 8 These out-of-pocket maximums, although important in protecting patients from catastrophic costs, will not help reduce medication abandonment because the abandonment stems from high initial out-of-pocket costs. With increasing drug list prices, patients exposed to deductible and coinsurance benefit The association between cost sharing, prior authorization, and specialty drug utilization: A systematic review while generally decreasing medication initiation and persistence. Similarly, programs that reduced patient cost sharing increased medication initiation and persistence. In contrast, patient cost sharing had an inconsistent and bidirectional effect on MPR and PDC. PA effects on specialty drug utilization varied. More research is needed to better understand the role of manufacturer copay offset programs on specialty drug utilization and to examine the effect of UM strategies on long-term health outcomes. the expected direction is that studies showing an insignificant association between cost and PDC/MPR would have been less likely to be funded by pharmaceutical manufacturers. However, it is possible that traditional publication bias exists if studies reporting an insignificant effect of cost sharing on specialty drug utilization were less likely to be published.

LIMITATIONS
There are several limitations of our study and the reviewed literature. First, the included studies may not have accounted for manufacturer copayment offset programs, which reduce patient cost sharing. Also, outcomes from studies that examined patient support programs may have been affected by broader patient support and not solely because of cost-sharing reductions. Second, different authors sometimes defined and measured the same outcome in different ways. For example, initiation was measured as starting the medication within 90 or 180 days. This limited our ability to combine some results. Third, most studies measured adherence via claims data. Claims data capturing medication dispensing may not always reflect actual patient medication use. Fourth, although most studies controlled for confounding variables such as demographics, comorbidities, and socioeconomic status, these control variables differed somewhat across studies and there may have been unmeasured confounders. Finally, we only included intermediate outcomes of specialty drug use, rather than health outcomes such as disease progression. Future research is needed to study the long-term effects of specialty drugs UM strategies on health outcomes.

Conclusions
Higher levels of patient cost sharing reduced specialty drug use by increasing medication abandonment The UM strategies of PA and cost sharing generally have been shown to reduce use of and adherence to specialty drugs. From a cost-saving perspective, one could argue that because reducing the use of specialty drugs decreases costs, the UM strategies are achieving their purpose. The more difficult question to answer is whether the cost savings comes at the expense of patient health outcomes. It is possible patients prescribed a specialty drug could have been successfully treated with a less expensive nonspecialty drug. Although not specific to specialty drugs, one study found that more than 75% of patients who abandoned a prescription failed to start any therapy within 90 days. 63 There is also evidence from the literature that nonadherence negatively affects patient outcomes. 34,37,[64][65][66][67][68] Given the environment of increasingly high drug prices, payers and policy makers need to carefully consider the impact of patient cost sharing on specialty drug adherence.

BIAS IN THE LITERATURE
Bias in published literature is always of concern. Many of the included studies were funded by pharmaceutical manufacturers. It was important to assess potential bias because pharmaceutical manufacturers theoretically would oppose drug benefit management strategies such as higher cost sharing and PA because these strategies may reduce use of their products. On one hand, more than half of the included studies related to adherence in this review were funded by pharmaceutical manufacturers. However, among the studies showed that patient cost sharing negatively impacted PDC, only 3 out of 6 studies disclosed funding by industry, 48,51,52 whereas all 3 studies showing insignificant or weak association between cost and PDC/ MPR were funded by pharmaceutical manufacturers. 50,56,57 If pharmaceutical manufacturer bias was a problem,